Abstract 362: Cell Cycle Defects of Hematopoietic Progenitor Cells in Rheumatoid Arthritis
Stuart M. Levine, MD
Authors:
I. Colmegna, L. Qian, H. Fujii, J. J. Goronzy, C. M. Weyand
Background:
This group has previously published compelling data that showed a dramatic reduction (by 50%) in circulating hematopoietic precursor cells (HPC) in RA patients, and that these cells bear the hallmark of increased proliferative stress and premature cellular aging- shortened telomere length. Whether these cells also have abnormalities in cell cycle progression is unknown.
Methods:
Circulating CD34+ HPCs from RA patients and controls were isolated and cultured in the presence of growth factors and a fluorescent label CFSE. DNA content , cell death rates, and growth factor receptor expression were analyzed by flow cytometry. Expression of specific regulators of differentiation and cell cycle progression were analyzed by real-time PCR.
Results:
HPCs from RA patients had a marked reduction in cell proliferation, and a higher percentage of cells that failed to enter the cell cycle. Growth factor receptor expression and apoptosis rates after stimulation were similar between the groups. Regulators of cell cycle progression were reduced in the RA group and these phenotypic abnormalities could not be restored after overnight culture in a non-inflammatory environment.
Editorial Comment:
This group has previously shown that one of the immunologic hallmarks of RA is the premature aging of their immune cells. In this study, they show that one of the mechanisms by which this occurs is via insufficient expression of specific cell cycle regulators such as cyclin D3 and c-myc, and not by impaired cell-surface signaling via growth factor receptors. Understanding the defects responsible for premature cellular aging in RA might facilitate the development of novel new therapies targeting this pathologic process.
